US9428542B2 - Lupane triterpenoid derivatives and pharmaceutical use thereof - Google Patents

Lupane triterpenoid derivatives and pharmaceutical use thereof Download PDF

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US9428542B2
US9428542B2 US14/374,832 US201314374832A US9428542B2 US 9428542 B2 US9428542 B2 US 9428542B2 US 201314374832 A US201314374832 A US 201314374832A US 9428542 B2 US9428542 B2 US 9428542B2
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dichloromethane
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US20150011517A1 (en
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Feng Lu
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FENG Qiaodi
JIANGXI QINGFENG PHARMACEUTICAL Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a novel lupane triterpenoid derivatives and pharmaceutical use thereof, specifically relates to a lupane triterpenoid derivatives of formula (I) ⁇ (III) and pharmaceutical use thereof, and further relates to a pharmaceutical composition and a combination preparation comprising a lupane triterpenoid derivatives or a pharmaceutically acceptable salt thereof in a therapeutically-effective dose, and the pharmaceutical use thereof, particularly relates to the uses in treatment of viral infection such as HIV-1/AIDS.
  • Maturation is an essential step in the life-cycle of HIV-1. It is the transition of the immature, non-infectious virus particle to the mature and infectious virion which represents as an excellent target for development of new class of anti-HIV-1 drugs.
  • lupane triterpenoid Some derivatives of lupane triterpenoid have been reported to have anti-HIV-1 activity, they bind to the preproteins (Gag) that specifically block HIV-1 protease to cleave p25 (CA-SPI) protein into their functional active form p24 (CA), resulting in the accumulation of the p25 (CA-SPI), immature and noninfectious HIV-1 virions that may prevent the subsequent cycles of HIV infection.
  • Gag preproteins
  • CA-SPI cleave p25
  • CA-SPI functional active form p24
  • immature and noninfectious HIV-1 virions immature and noninfectious HIV-1 virions that may prevent the subsequent cycles of HIV infection.
  • MI maturation inhibitors
  • Bevirimat (PA-457) is a new experimental agent to inhibit this last step of p25 (CA-SPI) protein being converted into the functional form p24 (CA). It has been reported that Bevirimat can reduce ART-resistant strains and wide type HIV viral load in patients, and has demonstrated synergy with antiretrovirals from all classes, but patients with Gag polymorphisms at Q369, V370, or T371 are resistant to this agent's therapy.
  • the present invention provides a novel lupane triterpenoid derivatives, or a pharmaceutically acceptable salt thereof, and pharmaceutical use thereof, particularly in their pharmaceutical use as a HIV maturation inhibitor; further to the use in preparing a medicament for the treatment of HIV infection and AIDS.
  • R 1 is independently H
  • X is independently methylene, carbonyl, thiocarbonyl, CHF, or CF 2 ;
  • L is independently a direct bond, —NR 4 —, -ethenyl-, -ethynyl-, —(CH 2 )r—, —CHOH—,
  • Y is independently a direct bond, —NR 4 —, —NR 4 —CH 2 —, —CHOH—,
  • Ar 1 is independently optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heterocycloalkyl, optionally substituted or unsubstituted heteroaryl, or optionally substituted or unsubstituted aminoalkyl; when substituted, the substituents could be one, two or three groups independently selected from the group consisting of: halo, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl, hydroxyalkyl, thioalkyl, —NHC(O)NH 2 , —NHC(O)NH(R 3 ), —N(R 3 )C(O)NH(R 3 ), —NHC(O)N(R 3 ) 2 , —N(R 3 )C(O)N(R 3 ) 2 , —NHC(O)NH(aryl), —NHC(O)NH
  • Ar 2 is independently optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heterocycloalkyl, or optionally substituted or unsubstituted heteroaryl; when substituted, the substituents could be one, two or three groups independently selected from the group consisting of: halo, haloalkyl, haloalkoxy, amino, —NHC(O)NH 2 , —NHC(O)NH(R 3 ), —N(R 3 )C(O)NH(R 3 ), —NHC(O)N(R 3 ) 2 , —N(R 3 )C(O)N(R 3 ) 2 , —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl), —NHSO 2 (R 3 ), —N(R 3 )SO 2 (R 3 ), —OH, —NO 2 , —SH, —S(O) 0-3 H,
  • R 3 is independently alkyl, or two R 3 together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocycloalkyl ring which could be optionally substituted with methylsulfonyl group or alkyl group;
  • R 4 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aminoalkyl, hydroxyalkyl, —S(O) 0-3 (R 3 ), —SO 2 NH 2 , —SO 2 NH(R 3 ), —(CH 2 )rS( ⁇ O)CH 3 , —(CH 2 )rS( ⁇ O) 2 CH 3 , —P(O)(O—R 3 ) 2 , —R 3 C(O)OH, HOOC—R 3 —C(O)—, HOOCC(CH 3 ) 2 CH 2 C(O)—, —C(O)O—R 3 , —C(O)—R 3 —NH 2 , —C(O)—R 3 —OH, —C(O)NH 2 ,
  • r is an integer from 1 to 8.
  • Said Aryl is a optionally substituted or unsubstituted phenyl group; said heterocycloalkyl is a 3-7-membered heterocycloalkyl group, and the heteroatom can be one, or more atoms independently selected from N, O, or S; said Heteroaryl is a 5-6-membered heteroaryl group. All of the representative example of them as describe below.
  • R 1 is independently H
  • X is independently methylene, carbonyl, thiocarbonyl, CHF, or CF 2 ;
  • L is independently a direct bond, —(CH 2 )r-, —CHOH—,
  • Y is independently a direct bond, —(CH 2 )—, —C( ⁇ O)—, —CH(CH 3 )—, —C(CH 3 ) 2 —, 1,1-cyclopropyldiyl, 1,1-cyclobutyldiyl, or 1,1-cyclopentyldiyl;
  • R 2 is independently hydrogen, halo, —OH, —NO 2 , amino, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, —C(O)OH, —C(O)O—R 3 , —C(O)NH 2 , —C(O)NH(R 3 ), or —C(O)N(R 3 ) 2 ;
  • Ar 1 is independently optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heterocycloalkyl, optionally substituted or unsubstituted heteroaryl, or optionally substituted or unsubstituted aminoalkyl; when substituted, the substituents could be one, two or three groups independently selected from the group consisting of: halo, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl, hydroxyalkyl, thioalkyl, —NHC(O)NH 2 , —NHC(O)NH(R 3 ), —N(R 3 )C(O)NH(R 3 ), —NHC(O)N(R 3 ) 2 , —N(R 3 )C(O)N(R 3 ) 2 , —NHC(O)NH(aryl), —NHC(O)NH
  • R 3 is independently alkyl, or two R 3 groups together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocycloalkyl ring which could be optionally substituted with methylsulfonyl group or alkyl group;
  • Z 1 is independently O, S, or NR 4 ;
  • R 4 is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aminoalkyl, hydroxyalkyl, —S(O) 0-3 (R 3 ), —SO 2 NH 2 , —SO 2 NH(R 3 ), —(CH 2 )rS( ⁇ O)CH 3 , —(CH 2 )rS( ⁇ O) 2 CH 3 , —P(O)(O—R 3 ) 2 , —R 3 C(O)OH, HOOC—R 3 —C(O)—, HOOCC(CH 3 ) 2 CH 2 C(O)—, —C(O)O—R 3 , —C(O)—R 3 —NH 2 , —C(O)—R 3 —OH, —C(O)NH 2 ,
  • r is an integer from 1 to 8.
  • R 1 is independently
  • R 2 is independently H, Cl, or CH 3 ;
  • X is independently methylene, or carbonyl
  • L is independently a direct bond, or —(CH 2 )—;
  • Z 1 is independently NR 4 ;
  • R 4 is independently —CH 3 , —C 2 H 5 , —CH 2 CH 2 NH 2 , or —CH 2 CH 2 N(CH 3 ) 2 ;
  • Y is independently a direct bond, or —CH 2 —;
  • Ar 1 is independently (R 5 )n-phenyl-, (R 5 )n-phenyl-CH 2 —, (R 5 )n-pyridyl-, (R 5 )n-pyridyl-CH 2 —, (R 5 )n-pyrimidyl-, (R 5 )n-pyrimidyl-CH 2 —, —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 COOH, —CH 2 CONH 2 , —CH 2 CONHCH 3 , or —CH 2 CON(CH 3 ) 2 ;
  • R 5 is independently methyl, methoxy, F, Cl, CN, or CF 3 ;
  • n is independently 0, 1, or 2.
  • R 1 is independently H
  • X is independently methylene, carbonyl, thiocarbonyl, CHF, or CF 2 ;
  • L is independently a direct bond, —NR 4 —, -ethenyl-, -ethynyl-, —(CH 2 )r-, —CHOH—,
  • Y is independently a direct bond, —NR 4 —, —NR 4 —CH 2 —, —CHOH—,
  • Z 2 , and Z 3 are independently O, N, or CH;
  • Z 4 is independently O, S, N, or NR 4 ;
  • Ar 1 is independently optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heterocycloalkyl, or optionally substituted or unsubstituted heteroaryl; when substituted, the substituents could be one, two or three groups independently selected from the group consisting of: halo, alkyl, alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl, hydroxyalkyl, thioalkyl, —NHC(O)NH 2 , —NHC(O)NH(R 3 ), —N(R 3 )C(O)NH(R 3 ), —NHC(O)N(R 3 ) 2 , —N(R 3 )C(O)N(R 3 ) 2 , —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl), —NHSO 2 (R 3 ), —N(R 3 )SO 2 (R 3
  • R 3 is independently alkyl, or two R 3 groups together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocycloalkyl ring which optionally substituted with methylsulfonyl group or alkyl group;
  • R 4 is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, aminoalkyl, hydroxyalkyl, —S(O) 0-3 (R 3 ), —SO 2 NH 2 , —SO 2 NH(R 3 ), —(CH 2 )rS( ⁇ O)CH 3 , —(CH 2 )rS( ⁇ O) 2 CH 3 , —P(O)(O—R 3 ) 2 , —R 3 C(O)OH, HOOC—R 3 —C(O)—, HOOCC(CH 3 ) 2 CH 2 C(O)—, —C(O)O—R 3 , —C(O)—R 3 —NH 2 , —C(O)—R 3 —OH, —C(O)NH 2 ,
  • r is an integer from 1 to 8.
  • R 1 is independently
  • X is independently methylene or carbonyl
  • L is independently a direct bond, —NR 4 —, —CHOH—,
  • Y is independently a direct bond, —NR 4 —, —NR 4 —CH 2 —, —CHOH—,
  • R 4 is independently H, or —CH 2 CH 2 N(CH 3 ) 2 ;
  • Z 2 , and Z 3 are independently N; Z 4 is O or S, that means
  • Ar 1 is independently (R 5 )n-phenyl-, (R 5 )n-phenyl-CH 2 —, (R 5 )n-pyridyl-, (R 5 )n-pyridyl-CH 2 —, (R 5 )n-pyrimidyl-, or (R 5 )n-pyrimidyl-CH 2 —;
  • R 5 is independently methyl, methoxy, F, Cl, Br, CN, or CF 3 ;
  • n is independently 0, 1, or 2.
  • X is independently methylene, or carbonyl
  • L is independently a direct bond, —CHOH—
  • Y is independently a direct bond
  • Z 2 , and Z 3 are independently N;
  • Z 4 is NR 4 , that means
  • R 4 is independently methyl, —CH 2 CH 2 NH 2 , —CH 2 CH 2 NHCH 3 , or —CH 2 CH 2 N(CH 3 ) 2 ;
  • Ar 1 is independently (R 5 )n-phenyl-;
  • R 5 is independently Cl
  • n 1.
  • X is independently methylene, or carbonyl
  • L is independently a direct bond
  • Y is independently a direct bond
  • Z 2 is N, Z 3 is CH, and Z 4 is O; or Z 2 is CH, Z 3 is N, and Z 4 is O, that means
  • Ar 1 is independently (R 5 )n-phenyl-;
  • R 5 is independently Cl
  • n 1.
  • X is independently methylene, or carbonyl
  • L is independently a direct bond or —CH 2 —;
  • Y is independently a direct bond
  • Z 2 is O, Z 3 , and Z 4 are independently N; or Z 3 is O, Z 2 , and Z 4 are independently N, that means
  • Ar 1 is independently (R 5 )n-phenyl-;
  • R 5 is independently Cl
  • n 1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one of compounds of the formula (I) ⁇ (III) as defined above, or a pharmaceutically acceptable salt thereof in a therapeutically-effective dose, as well as a pharmaceutical acceptable carrier, adjuvant, excipient, or vehicle.
  • the present invention provides any one of compounds of the formula (I) ⁇ (III) as defined above, or a pharmaceutically acceptable salt thereof for the use in preparation of a medicament for preventing or treating HIV-1 infections in a subject in need of a therapeutically-effective amount.
  • the present invention provides a combination preparation, which comprising any one of compounds of formula (I) ⁇ (III) as defined above, or a pharmaceutically acceptable salt thereof, the combination preparation can be used in anti-HIV combination therapies along with at least one further therapeutic drug, such as nucleoside/nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitor, entry inhibitor, and/or integrase inhibitors.
  • nucleoside/nucleotide reverse transcriptase inhibitor such as nucleoside/nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitor, entry inhibitor, and/or integrase inhibitors.
  • the pharmaceutical use of the compound of formula (I) ⁇ (III) of the present invention refers to anti-virus, especially in preparation of a medicament for preventing or treating HIV and AIDS.
  • alkyl refers to a saturated aliphatic hydrocarbon group including C 1 -C 20 straight chain and branched chain groups.
  • an alkyl group is a moderate size alkyl having 1 to 10 carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, n-hexyl, and the like.
  • it is a lower alkyl having 1 to 6 carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, or tert-butyl, pentyl, n-hexyl, and the like.
  • alkyl could be optionally substituted, that means the alkyl group which may be independently substituted by one to four substituents selected from the group consisting of halo, cycloalkyl, hydroxyl, mercapto, lower alkloxy, lower haloalkloxy, amino, amido, ureido, sulfonamido, methylsulfonyl, methylsulfinyl, aminocarbonyl, cyano, alkenyl, alkynyl, carboxylic acid, and carboxylic ester, aryl (optionally substituted with one or more groups which each independently is halo, cyano, hydroxy, carboxylic acid, lower alkyl, lower haloalkoxy, or lower alkoxy groups), aryloxy(optionally substituted with one or more groups which each independently is halo, cyano, hydroxy, carboxylic acid, lower alkyl, lower haloalkoxy, or lower alkoxy groups), heteroary
  • alkenyl refers to an alkyl group as defined above having at least 2 carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, 3-butenyl, and the like.
  • the optionally substituted alkenyl means the alkenyl which may be substituted with one or more groups which each independently is halo, cyano, lower alkyl or lower alkoxy groups.
  • alkynyl refers to an alkyl group as defined above having at least 2 carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, 3-butynyl, and the like.
  • the optionally substituted alkenyl means the alkynyl which may be substituted with one or more groups which each independently is halo, cyano, lower alkyl or lower alkoxy groups.
  • cycloalkyl refers to a 3 to 8 membered all-carbon monocyclic ring.
  • examples of cycloalkyl groups include but not limit to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, chcyclohexyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and the like.
  • the cycloalkyl group may be substituted or unsubstituted.
  • the substituent group(s) is preferably one or more independently selected from the group consisting of lower alkyl, haloalkyl, halo, hydroxy, hydroxyalkyl, aminoalkyl, carboxylic acid, lower alkoxy, lower haloalkoxy, amino, aminocarbonyl, sulfonamido, ureido, amido, methylsulfonyl, methylsulfinyl, cyano, amido, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, mercapto, or nitro; aryl(optionally substituted with one or more groups which each independently is halo, cyano, hydroxy, carboxylic acid, lower alkyl, lower haloalkoxy, or lower alkoxy groups); aryloxy(optionally substituted with one or more groups which each independently is halo, cyano, hydroxy, carboxylic acid, lower
  • halo refers to fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
  • cyano refers to a —C ⁇ N group.
  • hydroxy refers to an —OH group.
  • carboxylic acid refers to —COOH group.
  • thioalkyl refers to a -(alkyl)-SH and a -(unsubstituted cycloalkyl)-SH group.
  • Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
  • heterocycloalkyl refers to a mono-heterocycloalkyl with 4 to 7 ring atoms, wherein one, or two ring heteroatoms are selected from the group consisting of N, O, and S(O)n (n is integer from 0 to 2), the remaining ring atoms are C, in addition, the ring may also have one or more double bonds, but not have a completely conjugated pi-electron system.
  • heterocycloalkyl examples include but not limit to azetidyl, pyrrolidyl, piperidyl, piperazinyl, N-methyl-piperazinyl, 4-methyl-piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • the heterocycloalkyl may be substituted or unsubstituted.
  • the substituent group is preferably one or more, more preferably one, two, or three, further more preferably one or two groups, each independently selected from the group consisting of lower alkyl, cycloalkyl, lower hydroxyalkyl, haloalkyl, halo, hydroxy, aminoalkyl, carboxylic acid, lower alkoxy, lower haloalkoxy, cyano, amino, sulfonamido, methylsulfonyl, methylsulfinyl, ureido, and amido.
  • aryl refers to an optionally substituted phenyl.
  • the substituted group could be one or more groups and each independently selected from the group consisting of -alkylCOOH, carboxylic acid, halo, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkylthio, mercapto, nitro, amino, aminoalkyl, cyano, alkoxy and haloalkoxy, alkyl is defined as above.
  • substituted aryl include, but are not limited to, (R 5 )n-phenyl-, (R 5 )n-phenyl-CH 2 — etc., wherein R 5 is independently CH 3 , CH 3 O, F, Cl, CN, or CF 3 ; n is independently 0, 1, or 2.
  • heteroaryl refers to an optionally substituted heteroaryl having 1 to 4 heteroatoms selected from the group consisting of N, O, and S as ring atoms, the remaining ring atoms being C. Said heteroaryl is 5- or 6-membered ring.
  • the substituted group could be one or more groups and each independently selected from the group consisting of —(CH 2 ) 2 S(O)CH 3 , —(CH 2 ) 2 S(O) 2 CH 3 , -alkyl-C(O)OH, —COOH, acylamino, —CH 2 -amido, halo, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkylthio, mercapto, nitro, amino, aminoalkyl, cyano, alkoxy and haloalkoxy.
  • heteroaryl groups include but not limit to furyl, thienyl, pyrazolyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, pyrimidinyl, pyrazinyl, imidazolyl, triazolyl, tetrazolyl, oxatriazolyl, pyridazinyl, triazinyl,
  • R 5 n-pyridyl-, (R 5 )n-pyridyl-CH 2 —, (R 5 )n-pyrimidyl-, (R 5 )n-pyrimidyl-CH 2 — and the like.
  • Y, Ar 1 , R 2 , R 4 , R 5 , n are as defined above, (preferably R 4 is independently selected from the group consisting of methyl, ethyl, or
  • cycloalkylalkyl refers to a radical of the formula -RaRb, where Ra is an alkyl radical as defined above and Rb is a cycloalkyl radical as defined above.
  • the alkyl radical and the cycloalkyl radical may be optionally substituted as defined above.
  • Arylalkyl refers to a radical of the formula -RaRc where Ra is an alkyl radical as defined above and Rc is aryl radicals as defined above, e.g., benzyl, diphenylmethyl and the like.
  • the aryl radical(s) may be optionally substituted as described above.
  • Heterocycloalkylalkyl refers to a radical of the formula -RaRd where Ra is an alkyl radical as defined above and Rd is a heterocycloalkyl radical as defined above, and if the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl may be attached to the alkyl radical at the nitrogen atom or at carbon atom.
  • the alkyl part of the heterocycloalkylalkyl radical may be optionally substituted as defined above for an alkyl group.
  • the heterocycloalkyl part of the heterocycloalkylalkyl radical may be optionally substituted as defined above for a heterocycloalkyl group.
  • heteroarylalkyl refers to a radical of the formula -RaRe where Ra is an alkyl radical as defined above and Re is a heteroaryl radical as defined above.
  • the heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for a heteroaryl group.
  • the alkyl part of the heteroarylalkyl radical may be optionally substituted as defined above for an alkyl group.
  • methylene refers to CH 2 .
  • carbonyl refers to C( ⁇ O).
  • thiocarbonyl refers to C( ⁇ S).
  • amino refers to a —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NH-cyclopropyl, —NH-Ph, —NH-pyridyl, pyrrolidinyl, piperazinyl, N-methyl-morpholino, 4-methyl-piperazinyl, morpholino, piperidino, and the like.
  • amido refers to a —C( ⁇ O)NR f R f ′, which R f and R f ′ refer to amino substituents, R f and R f ′ may be the same or may not be same, which independently are hydrogen or alkyl, aryl, or heteroaryl (alkyl, aryl, and heteroaryl are as defined above)
  • Representative amido groups include, —C( ⁇ O)NH 2 , —C( ⁇ O)NHCH 3 , —C( ⁇ O)N(CH 3 ) 2 , —C( ⁇ O)NCH 3 CH 2 CH 3 , as well as the groups in which R f and R f ′ together with the nitrogen atom to which they are attached, form a heterocyclic ring, like morpholino, piperazinyl, piperidino, and the like.
  • aminocarbonyl including but are not limited to: —NHC( ⁇ O)CH 3 , —NCH 3 C( ⁇ O)CH 3 , —NHC( ⁇ O)CH 2 CH 3 , —NCH 3 C( ⁇ O)CH 2 CH 3 , —NHC( ⁇ O)-cyclopropyl, —NCH 3 C( ⁇ O)-cyclopropyl, —NHC( ⁇ O)Ph, —NCH 3 C( ⁇ O)Ph, and the like.
  • sulfonamido refers to —NR g S( ⁇ O) 2 R g ′, wherein R g is independently hydrogen or alkyl, and R g ′ is independently alkyl, aryl, or heteroaryl, alkyl, aryl, and heteroaryl are as defined above.
  • ureido refers to —NR h C(O)NR h ′R h ′′, wherein R h , R h ′, and R h ′′ are independently hydrogen or alkyl, and the alkyl as defined above, or R h ′ and R h ′′ together with the nitrogen atom to which they are attached, form a heterocyclic ring, like morpholino, piperazinyl, piperidino, and the like.
  • aminoalkyl refers to -alkyl-amino group, wherein alkyl and amino are as defined above, and may be optionally substituted.
  • the representative aminoalkyl group include but are not limited to
  • hydroxyalkyl refers to -alkyl-hydroxy group, wherein the alkyl could be optional substituted or unsubstituted as defined above.
  • the representative hydroxyalkyl group include but are not limited to —CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH.
  • haloalkyl refers to halo-alkyl group, wherein the halo and alkyl as defined above.
  • the representative haloalkyl group include but are not limited to —CF 3 , —CH 2 F, or —CHF 2 , and the like.
  • alkoxy refers to both an —O—[alkyl (lower alky)] and an —O-(unsubstituted cycloalkyl) group, alkyl, lower alkyl, and cycloalkyl groups are as defined above.
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • arylkoxy refers to —O-(aryl). Aryl as defined above.
  • haloalkoxy refers to an —O—[haloalkyl (lower haloalky)], halo, alkyl, and lower alkyl groups are as defined above. Representative examples include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, or tribromomethoxy, and the like. Halo and alkyl (lower alkyl) in haloalkyl (lower haloalkyl) are as defined above.
  • Two R 3 groups together with the nitrogen atom to which they are attached, may form a 3- to 7-membered heterocycloalkyl ring.
  • the examples include but not limit to pyrrolidyl, piperidyl, piperazinyl, N-methyl-piperazinyl, 4-methyl-piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like;
  • R 2 is H, Cl or methyl
  • R 4 is H, methyl, ethyl
  • r means an integer from 1 to 8, preferable 1 ⁇ 3, more preferable 1 or 2.
  • n means 0, 1 or 2.
  • Liane triterpenoid derivatives means the derivatives of Betulin.
  • aryl group optionally substituted with an alkyl group means that the alkyl may or may not be present, that is, the description includes situations wherein the aryl group is substituted with an alkyl group and situations wherein the aryl group is not substituted with an alkyl group.
  • hydrates refers to a compound provided herein or salts thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • solvates refers to a corresponding solvate of the present invention compound or salts thereof, formed from the combination of solvent molecules with the present invention compound or a salt thereof (or ions of the solute). If the solvent is water, the solvate may be simply referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • isomers refer to the stereoisomers like enantiomers, diastereomers, racemates, and the mixtures thereof.
  • the stereo chiral C of the present invention compounds of formula (I) ⁇ (III) is corresponding to the Betulin's, specific as follows:
  • prodrugs refers to a compound which, when metabolized in vivo, converts back to the original active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.
  • pharmaceutical composition refers to a mixture of one or more of the compounds of formula (I) as described in present invention herein, or hydrates, or solvates, or isomers, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and recipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to warm blood animals and human.
  • the compounds of the present invention were synthesized from the commercially available natural occurring compound Betulin 1 as a key intermediate. Wherein the synthesis of key intermediates 6, 12, and 15 from Betulin, see the following steps:
  • the resulting mixture contained compound 2 (23.8 g, 45.18 mmol) from above was heated to 105° C., then sequentially added a solution of HBr in acetic acid (33%) (40 ml), toluene (40 ml), acetic anhydride (40 ml) and acetic acid (40 ml). The reaction mixture was stirred at this temperature for 1.5 h. After cooling down to room temperature, sodium acetate (8 g) was added and the mixture was evaporated to dryness.
  • Method 18 Compound 153-1, 153′-1, 155-1 ⁇ 155-2, 155′-1, 156-1 ⁇ 156-2, and 156′-1 were prepared according to scheme 18.
  • the compounds of the present invention may be in crystalline or non-crystalline form, it may exist in a number of different polymorphic forms, and may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amount of water.
  • non-toxic salts include conventional non-toxic salts, e.g. from non-toxic inorganic or organic acids or inorganic bases.
  • non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, benzoic, succinic, glycolic, gluconic, stearic, lactic, maleic, tartaric, citric, succinic, salicylic, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, formic, naphthalene-2-sulphonic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, triflu
  • pharmaceutically acceptable salts can be prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base, in a suitable solvent or solvent combination.
  • the analytical low-resolution mass spectra (MS) were recorded on Agilent 1200 HPLC/6110 using a SunFire C18, 4.6 ⁇ 50 mm, 3.5 ⁇ m using a gradient elution method.
  • the gradient elution method is: 80-5% solvent A and 20-95% solvent B for 1.8 mins, then solvent B and 5% solvent A 3 mins or more.
  • Solvent A 0.01% trifluoroacetic acid (TFA) in water.
  • Solvent B 0.01% TFA in acetonitrile
  • TLC HSG-254 plates and GF254 plates.
  • DIPEA ethyldiisopropylamine
  • HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • PCC pyridinium chlorochromate
  • DIAD diisopropyl azodicarboxylate
  • Example 1-18 (Compounds 22-1 ⁇ 22-18 were prepared according to method 1 and scheme 1 by using different acid intermediates like 16 and the like)
  • Compound 22-2 was prepared according to scheme 1 and method 1, as an off-white solid.
  • Compound 22-3 was prepared according to method 1 and scheme 1, as an off-white solid.
  • Compound 22-4 was prepared according to method 1 and scheme 1, as an off-white solid.
  • Compound 22-5 was prepared according to method 1 and scheme 1, as an off-white solid.
  • Compound 22-6 was prepared according to method 1 and scheme 1, as an off-white solid.
  • Compound 22-7 was prepared according to method 1 and scheme 1, as an off-white solid.
  • Compound 22-8 was prepared according to method 1 and scheme 1, as an off-white solid.
  • Compound 22-9 was prepared according to method 1 and scheme 1, as an off-white solid.
  • Compound 22-10 was prepared according to method 1 and scheme 1, as an off-white solid.
  • Compound 22-11 was prepared according to method 1 and scheme 1, as an off-white solid.
  • Compound 22-12 was prepared according to scheme 1 and method 1, as an off-white solid.
  • Compound 22-13 was prepared according to scheme 1 and method 1, as an off-white solid.
  • Compound 22-14 was prepared according to method 1 and scheme 1, as an off-white solid.
  • Compound 22-15 was prepared according to method 1 and scheme 1, as a white solid.
  • Compound 22-16 was prepared according to method 1 and scheme 1, as a white solid (5-chloropyrimidine-2-carboxylic acid was prepared according to US2007270438A1 and WO200528452A1).
  • Compound 22-17 was prepared according to method 1 and scheme 1, as an off white solid.
  • Compound 22-18 was prepared according to method 1 and scheme 1, as an off white solid.
  • Example 19-32 (Compound 27-1 ⁇ 27-14 were prepared according to method 1 and scheme 2 by using different acid intermediates like 16 and the like)
  • Compound 27-2 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-3 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-4 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-5 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-6 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-7 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-8 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-9 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-10 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-11 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-12 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-13 was prepared according to method 2 and scheme 2, as an off-white solid.
  • Compound 27-14 was prepared according to method 2 and scheme 2, as an off white solid.
  • Example 33 (Compound 33 was prepared according to method 3 and scheme 3)
  • Example 34 (Compound 38 was prepared according to method 4 and scheme 4)
  • Example 35-36 (Compound 54-1 ⁇ 54-2 was prepared according to method 5 and scheme 5)
  • Compound 54-2 was prepared according to method 5 and scheme 5, as an off-white solid.
  • Example 37-39 (Compound 59-1 ⁇ 59-3 was prepared according to method 6 and scheme 6)
  • Compound 59-2 was prepared according to method 6 and scheme 6, as an off-white solid.
  • Compound 59-3 was prepared according to method 6 and scheme 6, as an off-white solid.
  • Example 40 (Compound 65 was prepared according to method 7 and scheme 7)
  • Example 41 (Compound 70 was prepared according to method 8 and scheme 8)
  • Example 42 (Compound 77 was prepared according to method 9 and scheme 9)
  • Example 43-60 (Compound 89-1 ⁇ 89-7, 89′-1, 91-1 ⁇ 91-9 and 91′-1 were prepared according to method 10 and scheme 10, by using different alkylating intermediates like 86 and the like.)
  • Compound 89-2 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 89-3 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 89-4 was prepared according to method 10 and scheme 10, as an pink solid.
  • Compound 89-5 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 89-6 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 89-7 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 89′-1 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 91-2 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 91-3 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 91-4 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 91-5 was prepared according to method 10 and scheme 10, as a pink solid.
  • Compound 91-6 was prepared according to method 10 and scheme 10 as a white solid.
  • Compound 91-7 was prepared according to method 10 and scheme 10, as a white solid.
  • Compound 91-8 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 91-9 was prepared according to method 10 and scheme 10, as an off-white solid.
  • Compound 91′-1 was prepared according to method 10 and scheme 10, as a white solid.
  • Example 61-73 (Compound 96-1 ⁇ 96-2, 96′-1, 98-1 ⁇ 98-8, and 98′-1 ⁇ 98′-2 were prepared according to method 11 and scheme 11 by using different boronic acid intermediates like 92 and the like.)
  • Compound 96-2 was prepared according to method 11 and scheme 11, as an off-white solid.
  • Compound 96′-1 was prepared according to method 11 and scheme 11, as a white solid.
  • Compound 98-2 was prepared according to method 11 and scheme 11, as an off-white solid.
  • Compound 98-3 was prepared according to method 11 and scheme 11, as an off-white solid.
  • Compound 98-4 was prepared according to method 11 and scheme 11, as a light yellow solid.
  • Compound 98-5 was prepared according to method 11 and scheme 11, an off-white solid.
  • Compound 98-6 was prepared according to method 11 and scheme 11, as an off-white solid.
  • Compound 98-7 was prepared according to method 11 and scheme 11, as a white solid.
  • Compound 98-8 was prepared according to method 11 and scheme 11 by substituting 94-1 with 94-8, as an orange solid.
  • Compound 98′-1 was prepared according to method 11 and scheme 11, as an off-white solid.
  • Compound 98′-2 was prepared according to method 11 and scheme 11, as a light yellow solid.
  • Example 74 (Compound 102 was prepared according to method 12 and scheme 12)
  • Example 75-76 (Compound 108-1 ⁇ 108-2 were prepared according to method 13 and scheme 13)
  • Compound 108-2 was prepared according to method 13 and scheme 13, as off white solid.
  • Example 77-80 (Compound 116-1 ⁇ 116-4 were prepared according to method 14 and scheme 14)
  • Compound 116-2 was prepared according to method 14 and scheme 14, as a white solid.
  • Compound 116-3 was prepared according to method 14 and scheme 14, as a white solid.
  • Compound 116-4 was prepared according to method 14 and scheme 14, as a white solid.
  • Example 81-85 (Compound 127-1 ⁇ 127-5 were prepared according to method 15 and scheme 15 by using different hydrazide intermediates like 119 and the like.)
  • reaction mixture was stirred at 0 for 1 h, then diluted with dichloromethane (100 ml), washed with water (10 ml ⁇ 3), brine, dried over sodium sulfate, filtered and concentrated to afford crude compound 124-1 (40 mg, 100%) as an off-white solid, used directly in next step without the further purification.
  • Compound 127-2 was prepared according to method 15 and scheme 15, as an off-white solid.
  • Compound 127-3 was prepared according to method 15 and scheme 15, as an off-white solid.
  • Compound 127-4 was prepared according to method 15 and scheme 15, as an off-white solid.
  • Compound 127-5 was prepared according to method 15 and scheme 15, as a yellow solid.
  • Example 86-88 (Compound 133-1 ⁇ 133-3 were prepared according to method 16 and scheme 16)
  • Compound 133-3 was prepared according to method 16 and scheme 16, as an off white solid.
  • Example 89-91 (Compound 141-1 ⁇ 141-3 were prepared according to method 17 and scheme 17)
  • Compound 141-2 was prepared according to method 17 and scheme 17, as an off-white solid.
  • Compound 141-3 was prepared according to method 17 and scheme 17, as a white solid.
  • Example 92-97 (Compound 153-1, 153′-1; 155-1; 155-2, 155′-1; 156-1, 156-2, and 156′-1 were prepared according to method 18 and scheme 18)
  • reaction mixture was stirred for another 2 h, diluted with ethyl acetate (30 ml), washed with water and brine, dried over sodium sulfate, filtered and concentrated and purified by Prep-TLC (5% MeOH in DCM) to afford compound 153-1 (2 mg, yield 43%) as an off-white solid.
  • Compound 153′-1 was prepared according to method 18 and scheme 18, as an off white solid.
  • Compound 155-2 was prepared according to method 18 and scheme 18 by substituting 151-1 with 151-2, as an off white solid.
  • Compound 155′-1 was prepared according to method 18 and scheme 18, as an off white solid.
  • Compound 156-2 was prepared according to method 18 and scheme 18 by substituting 151-1 with 151-2, as an off white solid.
  • Compound 156′-1 was prepared according to method 18 and scheme 18, as an off white solid.
  • Example 100-103 (Compound 164-1, 164-2, 165-1 and 165-2 were prepared according to method 19 and scheme 19)
  • Compound 164-2 was prepared according to method 19 and scheme 19, as a white solid.
  • Compound 165-2 was prepared according to method 19 and scheme 19, as an off white solid.

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EP2812343B1 (de) 2019-03-13
JP5872074B2 (ja) 2016-03-01
WO2013117137A1 (en) 2013-08-15
BR112014018953A2 (de) 2017-06-20
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BR112014018953A8 (pt) 2017-07-11
CA2860581A1 (en) 2013-08-15
AU2013218441A1 (en) 2014-07-24
EP2812343A4 (de) 2015-12-02
EA201491479A1 (ru) 2014-11-28
EP2812343A1 (de) 2014-12-17
JP2015505545A (ja) 2015-02-23

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